Bile-pancreatic juice (BPJ) exclusion exacerbates Akt/NF-kB pathway activation and increases chemokine production in ligation-induced acute pancreatitis

Abstract

Abstract Introduction: Using a unique surgical model (The Donor Rat Model) we showed that duodenal replacement of BPJ, obtained fresh from a Donor Rat, ameliorates pancreatic morphologic changes, hyperamylasemia and hypercholecystokininemia in ligation-induced acute pancreatitis. We hypothesize that BPJ exclusion from gut exacerbates Akt/NF-kB pathway activation and induces proinflammatory chemokine production in ligation-induced acute pancreatitis. The cytosolic IkB/NF-kB complex dissociates when IkB is phosphorylated following Akt activation, allowing NF-kB to translocate to the nucleus and induce transcription of various inflammatory mediators including chemokines. Methods: We studied rats as follows: Diseased-controls had bile-pancreatic duct ligation. Diseased-treated rats had duodenal BPJ replacement fresh from a Donor Rat beginning immediately before duct ligation. Sham controls had ducts dissected only. Rats were killed after 1 or 3 hours (n = 7/group). Pancreatic homogenates were used to determine Akt activation (immunoblotting, immunecomplex kinase assay and ELISA), IkB activation (immunoblotting), and production of chemokines MCP-1 and RANTES (ELISA). NF-kB was quantitated in pancreatic nuclear fractions using EMSA. Results: Compared to sham, duct ligation was associated with marked increases in pancreatic Akt and IkB activation, NF-kB nuclear translocation, and MCP-1 and RANTES production. Akt/NF-kB pathway activation and increased MCP-1 and RANTES production after duct ligation were substantially ameliorated by BPJ replacement (ANOVA, p Conclusions: BPJ exclusion from gut exacerbates Akt/NF-kB pathway activation and increases chemokine production in ligation-induced acute pancreatitis. These findings support our central hypothesis that BPJ exclusion-induced acinar cell hyperstimulation exacerbates acute pancreatic inflammation in this experimental corollary of gallstone-induced acute pancreatitis. (Support: ACS Faculty Research Fellowship, NIH-K08 Award#DK062805)